| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of this 8-week study is to evaluate the dose response, efficacy and safety of four dosage regimens of GW685698X (200mcg, 400mcg, 600mcg and 800mcg) administered once daily in the evening in adolescent and adult subjects 12 years of age and older with persistent uncontrolled asthma to effectively select the appropriate dose of GW685698X to be evaluated in further clinical studies. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Type of Subject: Outpatient
2. Age: 12 years of age or older at Visit 1. For sites in the following countries, subjects recruited will be ≥18 years of age: Bulgaria, Czech Republic, Germany, Greece, Lithuania, New Zealand, Russian Federation, Turkey and any other countries where local regulations or the regulatory status of study medication permit enrolment of adults only.
3. Gender: Male or Eligible Female
• To be eligible for entry into the study, females of childbearing potential must
commit to consistent and correct use of an acceptable method of birth control, as
defined by the following:
• Male partner who is sterile prior to the female subject’s entry into the study
and is the sole sexual partner for that female subject
• Implants of levonorgestrel
• Injectable progestogen
• Oral contraceptive (either combined estrogen/progestin or progestin only)
• Any intrauterine device (IUD) with a documented failure rate of less than 1% per year.
• Females of childbearing potential who are not sexually active must commit to
complete abstinence from intercourse throughout the clinical trial and for a
period after the trial to account for elimination of the drug (minimum of six days).
• Double barrier method – spermacide plus a mechanical barrier (e.g., spermacide plus a male condom or a spermacide and female diaphragm).
• NB: For German sites, female subjects must use a method of birth control
other than the double barrier method.
• The contraceptive transdermal patch, Ortho Evra (if the subject is less than 198 pounds)
• Female subjects should not be enrolled if they are pregnant, lactating or plan to
become pregnant during the time of study participation. A serum pregnancy test
is required of all females. This test will be performed at the initial screening
visit (Visit 1) and Visit 8. In addition, a urine pregnancy test will be performed
on the evening of the double-blind treatment visit, prior to randomization (Visit
3) and at Visits 4 through 7.
4. Asthma Diagnosis: Asthma as defined by the National Institutes of Health
[National Institutes of Health (NIH), 2007].
5. Severity of Disease: A best FEV1 of 40%-90% of the predicted normal value during
Visit 1. NHANES III predicted values will be used for subjects aged ≥ 12 years and
adjustments to predicted values will be made for African American subjects.
[Hankinson, 1999].
6. Reversibility of Disease: Demonstrated a ≥ 12% and ≥200mL reversibility of FEV1
within 30-minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol
(if required, spacers are permitted for reversibility testing only) or one nebulized
albuterol/salbutamol solution at the Screening Visit. If a subject fails to demonstrate
an increase in FEV1 ≥12% and ≥200mL, then the subject is not eligible for the study
and will not be allowed to re-screen.
7. Current Anti-Asthma Therapy: Subjects must have been maintained on a stable
dose of inhaled corticosteroids for four weeks prior to Visit 1 at one of the following
doses:
Asthma Therapy Maximum Daily Dose (mcg/day)
fluticasone propionate MDI CFC/HFA >176 ≤ 440mcg (1) / > 200 ≤ 500mcg (2)
fluticasone propionate DPI > 200 ≤ 500mcg
beclomethasone dipropionate DPI > 420 ≤ 840mcg (1)/ > 500 ≤ 1000mcg (2)
beclomethasone dipropionate HFA (Qvar) > 160 ≤ 480mcg (1)/ > 200 ≤ 500mcg (2)
budesonide DPI MDI > 400 ≤ 1200mcg
flunisolide > 1000 ≤ 2000mcg
triamcinolone acetonide > 1000 ≤ 1600mcg
mometasone furoate DPI > 200 ≤ 440mcg
ciclesonide MDI HFA >160 mcg ≤ 320mcg1 / >200mcg ≤ 400mcg( 2)
(1). Ex-actuator dose
(2). Ex-valve dose
8. Short- Acting Beta2-Agonists: All subjects must be able to replace their current
short-acting beta2-agonists with albuterol/salbutamol inhalation aerosol at Visit 1 for
use as needed for the duration of the study. The use of spacer devices with metered
dose inhaler (MDI) or nebulized albuterol/salbutamol will not be allowed during the
study with the exception of their use during reversibility testing at Visit 1. Subjects
must be able to withhold all inhaled short-acting beta sympathomimetic
bronchodilators for at least 6 hours prior to all study visits.
9. Informed Consent: All subjects must be able and willing to give written informed
consent to take part in the study.
10. Compliance: Subjects must be able to comply with completion of the Daily Diary
(includes paper medical conditions diary).
11. French subjects: In France, a subject will be eligible for inclusion in this study only
if either affiliated to or a beneficiary of a social security category.
|
|
| E.4 | Principal exclusion criteria |
1. History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures.
2. Respiratory Infection: Culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1. In addition, the subject must be excluded if such infection occurs between Visits 1 and 3.
3. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids within 3 months of Visit 1. A subject must not have had any hospitalization for asthma within 6 months prior to Visit 1.
4.Concurrent Diseases/Abnormalities: Historical or current evidence of clinically
significant uncontrolled disease including, but not limited to: cardiovascular
disease, hepatic disease, renal disease, hematological disease, neurological disease,
or pulmonary disease (including, but not confined to chronic bronchitis,
emphysema, bronchiectasis with the need of treatment, cystic fibrosis,
bronchopulmonary dysplasia, and chronic obstructive pulmonary disease).
Significant is defined as any disease that, in the opinion of the investigator, would
put the safety of the subject at risk through participation, or which would affect the
efficacy or safety analysis if the disease/condition exacerbated during the study. Further excluded conditions/diseases are listed in section 4.3 of the protocol.
5. Oropharyngeal Examination: A subject will not be eligible for the run-in if
he/she has clinical visual evidence of oral candidiasis at Visit 1.
6.Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1.
7. Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the novel dry powder inhaler or DISKUS/ACCUHALER (i.e. lactose or magnesium stearate).
8. Milk Protein Allergy: History of severe milk protein allergy.
9. Immunosuppressive Medications: A subject must not be using, or require use, of immunosuppressive medications during the study. (Note: Immunotherapy for asthma allowed provided initiated prior to visit 1 and the subject is maintained on a stable regimen throughout the study period).
10. Attendance: A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, or geographical location which seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliant with study medication or procedures (e.g. completion of daily diary). Neurological or
psychiatric disease or history of drug or alcohol abuse which in the opinion of the
investigator could interfere with the subject’s proper completion of the protocol
requirements excludes study participation.
11. Tobacco Use. Current smoker or a smoking history of 10 pack years or more (e.g.
20 cigarettes/day for 10 years). A subject may not have used tobacco products within the past one year.
12. Affiliation with Investigator’s Site: A subject will not be eligible for this study if
he/she is an immediate family member of the participating Investigator,
sub-Investigator, study coordinator, or employee of the participating Investigator.
13. Corticosteroid Use:
• Administration of systemic, oral or depot corticosteroids within 12 weeks of
Visit 1.
14. Potent Cytochrome P450 3A4 (CYP3A4) inhibitors: Patients who are receiving
potent CYP3A4 inhibitors within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole,
itraconzole).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Mean change from baseline to the end of the 8-week treatment period (last
assessment on treatment using last observation carried forward) in trough (PM predose and pre- rescue bronchodilator) FEV1..
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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